Addressing threats to health care's core values, especially those stemming from concentration and abuse of power. Advocating for accountability, integrity, transparency, honesty and ethics in leadership and governance of health care.

Tuesday, August 19, 2008

Bad Seed: the ADVANTAGE Trial of Vioxx

An article in the Annals of Internal Medicine by Hill et al(1), and the accompanying editorial by Sox and Rennie(2) have created quite a stir in the media and blogsphere. Even so, it seems worth reviewing the main points, and adding some comments.

Hill et al address the ADVANTAGE trial, published in the Annals in 2003.(3) This was a randomized controlled trial that compared rofecoxib (Vioxx, by Merck) to naproxen for patients with osteoarthritis. 600 investigators each enrolled a few (target 6) patients. The trial failed to show that rofecoxib had any advantage of naproxen in terms of pain relief (see our discussion here). Long after the trial report was published, it turned out that its first author had no involvement in the study until Merck presented him with a copy of the manuscript written by company authors describing it, making it one of the more prominent recent examples of ghost-writing (see post here).

Hill et al obtained access to numerous internal Merck documents that only came to light in response to discovery requests filed in litigation. They appear to show that the ADVANTAGE trial was actually a "seeding" trial, designed to market the drug by putting "its product in the hands of practicing physicians, hoping that the experience of treating patients with the study drug and a pleasant, even profitable interaction with the company will result in more loyal physicians who prescribe the drug." In support of that, they found these themes in the documents they examined.

- "The trial emerged from the marketing division with a marketing objective;"- "Merck's marketing division collected, analyzed, and disseminated both the scientific and the marketing data; and"- "Merck did not reveal the marketing purposes of the trial to participants, physician-investigators, and institutional review board members."

Remarkably, an internal Merck memo made these further points:

First, the trial was targeted to a select group of critical customers.

[These were] primary care physicians. The ADVANTAGE trial utilized this important group as investigators.

Second, the design of the trial focused on demonstrating the value of VIOXX to this important audience

So, the study was designed primarily not to answer a clinical or scientific question, but to target certain physicians as "customers."

Third, execution of the trial ... [involved] integration of the field, marketing, and CDP [Clinical Development Program].

Thus, the study was really run by marketers, not scientists of clinicians.

Also,

Finally, the results of the trial are being carefully tracked. An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers....

Thus, the primary subjects of the trial were really not the patients, but the "investigators." Really, this was a trial that showed that involving primary care physicians as "investigators" in a seeding trial caused them to prescribe the supposed study drug more often than physicians not involved in the trial.

Nonetheless, informed consent forms for the trial did not inform subjects of its underlying marketing objectives.

This article appears to be the first to provide evidence that pharmaceutical companies may deliberately disguise marketing efforts as clinical research. This is a real achievement, since obviously the companies involved make every effort to hide what they are doing, and it only through discovery during litigation did the facts come out.

The authors conclude that

At least 3 elements of seeding trials are harmful to science and society. First, full informed consent is not possible without disclosing the full purpose of the trial. Physicians and patients participating in ADVANTAGE were informed of the scientific objectives of the study, but the research protocol and informed consent templates indicate that they were not told about the key role of Merck's marketing division in the trial or the true purpose of the trial. Second, good research practice is at risk when the marketing division designs and conducts a study. In a seeding trial, in order to fulfill strong marketing objectives, the recruitment of several research sites with fewer patients per site may result in less quality control from investigators and use of sites that have less research experience than academic centers or community physicians' offices, which may be more accustomed to hosting clinical trials. Quality control and rigorous research conduct may not receive adequate attention when marketing is the primary purpose of the study. Third, the study may have little scientific merit. Around the same time as ADVANTAGE, Merck launched the VIGOR (Vioxx Gastrointestinal Outcomes Research) trial to be the definitive study of gastrointestinal toxicity. The FDA required Merck to conduct VIGOR before putting claims of improved gastrointestinal safety on the Vioxx label. Thus, the purpose of ADVANTAGE was neither to seek a new indication nor to perform postmarketing surveillance.

Additionally,

Failure to disclose the primary purpose of a trial has ethical ramifications for patients, physicians, and the design of clinical trials. Seeding trials like ADVANTAGE, in which the study medication has yet to receive FDA approval, may cause patient injury for marketing purposes.

The primary marketing objectives of seeding trials are hidden from the public, the medical profession, and institutional review board members, preventing them from making a fully informed decision about the balance of benefits and harms to themselves and society.

The importance of the article by Hill et al, in my humble opinion, goes beyond its clear demonstration that seeding trials do exist. The article demonstrates how clinical research may be twisted into marketing. The article demonstrates how an ostensibly scientific endeavor may be based on deception, when science is supposed to be about the pursuit of truth. The article demonstrates how the ethos of the huckster has replaced that of the physician in large organizations once regarded as ethical.

Once again, this is a reminder that patients, physicians and policy makers must be extremely skeptical of clinical research sponsored by organizations which have something to gain if the research turns out a certain way. Furthermore, it is a reminder to physicians that generous offers from organizations selling products, services or ideologies do not arise from altruism.

As Sox and Rennie suggest, physicians should "just say no" to seeding trials. Maybe it is time for society to "just say no" to letting those with products to sell run experiments on humans to test them.

I am surprised that you criticize Yale and the author of the Annals article for leftism, but take a leftist stance yourself (that the ends justifies the means if no harm was done).

Ed Scolnick, the head of R&D wrote that the study was a small marketing study and intellectually (i.e., scientifically) redundant. It was also deceptive of its participants. It should not have been performed.

Can we agree that some harm has to take place before punishments or before new regulations?

It is pretty clear that Vioxx is not a better pain reliever than other non-steroidal anti-inflammatory drugs, and has, at best, only slightly fewer gastrointestinal adverse reactions. (See this post: http://hcrenewal.blogspot.com/2007/03/drug-crazy.html) And it seems to cause an increased risk of serious cardiac adverse reactions.

Thus, giving Vioxx to a general population of patients with mild-to-moderate pain, as Merck's marketing promoted, would likely have caused some to have serious cardiac events they would not have otherwise had, without giving them any major benefits they would not have had taking other NSAIDs.

The "seeding" trial, based on Merck's own internal memos, was meant to increase use of Vioxx by primary care doctors for such patients. Furthermore, Merck had data that it actually did increase its use. Thus, the trial itself likely caused some patients to have adverse cardiac events, although it may not be possible to tell which patients who had such events had them due to Vioxx.

There thus appears to be an argument that this trial caused harm, although we cannot identify to whom.

"No harm, no foul"? No way. This wasn't about researchers doing good science and by the way advancing their careers, this was about pushing a product first and foremost, and doing so by deliberately concealing the fact that that was what it was about. Had people been honestly informed of the purpose (not the secondary benefit, the primary purpose) of this study, few would have enrolled in it. Human beings were deceived into serving as study subjects. That is a per se violation of research ethics. One need not be able to point to specific individuals who suffered physical injury. The deception itself was unethical.

Dr. Poser is censoring my comments. All research is for the benefit of others, including the ulterior motives of the researcher. One does not put in the consent, the aim of this project is to qualify the researcher for a Ph.D, otherwise the researcher does not give a rat's ass about the findings.

Dr. Poses: Double sincere apologies. I misspelled your name, and mistakenly alleged censorship. I commend your courage in allowing dissent from the extreme left wing ideologue claims here. Many other sites not only censor, but permanently ban the dissenter.

By definition, research is for the benefit of others. If the treatment is for the benefit of the subject, it is called clinical care, however speculative. Payment to the subject for participation is likely the sole benefit to the subject.

Ulterior motives are numerous, normal, and almost never stated. Promoting the career of the research, qualifying for a degree, making money, getting famous, attacking an enemy's theory. So hidden pretexts are the norm, and not unethical or aberrant.

Here are some substantive problems caused by left wing attacks on corporations and by their lawyers.

Only about 5% of people in the target group ever qualify for participation. The vast majority get excluded. In highly sophisticated studies seeking to take all comers randomly, the figure goes up to 10%. This makes all studies garbage science, violating the central assumption of parametric statistics, random selection.

Thank the left wing research basher, the IRB extreme obstructionists, and the plaintiff tort lawyer for making all human research garbage.

By your wrongheaded bashing of drug company research, you have added to the heap of garbage.

Ulterior motives are numerous, normal, and almost never stated. Promoting the career of the research, qualifying for a degree, making money, getting famous, attacking an enemy's theory. So hidden pretexts are the norm, and not unethical or aberrant.

Hidden pretexts are not unethical?

The oath of Hippocrates does not say "I will do what's best for my patient as long as it benefits me too, and the patient understands I have a hidden agenda anyway so it's OK."

In fact, your view on this issue leans highly to the left, i.e., seems highly characterized by moral relativism.

I am having trouble getting the ideologues here to see the difference between clinical care and research.

In research, outside of money for time and inconvenience, the benefit is for others. The research subject is a service provider, not a recipient of care.

The Hippocratic Oath applies to patients.

Here is a moral standard from the Nuremberg Principles. Would the researcher allow himself to become a research subject in his proposed experiment? He should attest to that. Outside of lawyer gotcha, left wing bias and anti-corporate animus, what objection would you have to participating in the experiment? What physical harm would you have suffered?

My name is Tina Harris and i would like to show you my personal experience with Vioxx.

I am 40 years old. Have been on Vioxx for 6 months now. I had quit taking Vioxx long before the recall because it was the only new med introduced into my regimen at the time the symptoms started. I was told that if I continued to take it, I would be let go from my job because of inability to perform simple tasks.

I have experienced some of these side effects -vertigo, diarrhea, abdominal pain, respiratory problems and memory loss. I still have memory loss and have gaps in my thinking process where I can't even think of common words I am trying to say, even to this day.

Merck has a history of creating with deliberate intent very toxic seeding trials.

These are trials that are disguised as science-seeking peer-reviewed journals.

In actuality, such clinical trials are merely marketing outlets to fulfill marketing objectives.

Created by the marketing divisions of typically large pharmaceutical companies, this division handles all data acquired from their jigsaw trial.

They also do not disclose the purpose of the trial to the trial participants.

Merck’s ADVANTAGE trial, which began soon after Vioxx got approved was the first documentary evidence that proved the existence of seeding trials, and was published in the Archives of Internal Medicine after its completion.

An editorial from the staff of the journal followed- illustrating that this trial is, in fact, a seeding trial.

Merck responded to this editorial expressing shock and disbelief- stating that had only the authors and editors of the clinical trial contacted Merck about the fallacies illustrated in the trial and editorial, then all would see the true benefit and intentions with the ADVANTAGE trial.

Yet, according to Merck, these gifted annotators chose not to contact them for Merck to review their work. Therefore, the study is flawed due to those not as competent as Merck.

Contact Us

Email: info at firmfound dot org
or go to the web-site for FIRM - the Foundation for Integrity and Responsibility in Medicine

More About FIRM and Health Care Renewal

FIRM - the Foundation for Integrity and Responsibility in Medicine is a 501(c)3 that researches problems with leadership and governance in health care that threaten core values, and disseminates our findings to physicians, health care researchers and policy-makers, and the public at large. FIRM advocates representative, transparent, accountable and ethical health care governance, and hopes to empower health care professionals and patients to promote better health care leadership.

FIRM depends on contributions from individuals and non-profit organizations. FIRM does not accept any direct support from for-profit health care corporations.

FIRM welcomes support from individuals and non-profit organizations. If you are interested in donating to FIRM, please email info at firmfound dot org, snail mail us at 16 Cutler St, Suite 104, Warren, RI, 02885, USA, or see our web-site.

Subscribe To Health Care Renewal

Policies: Blog Roll and Comments

Our blogroll is meant to include blogs that provide interesting content relevant to what we write. It is not an endorsement in any way of any specific blog.

We accept comments, especially from registered Blogger users. If you do not wish to register with Blogger, we will accept anonymous comments, although prefer that they contain identification of the commenter.

We encourage thoughtful comments relevant to the issues brought up by the posts on Health Care Renewal.

All comments are moderated. We will reject spam, profanity, advertising of products or services not directly related to the content of this blog.

We will reject any unsubstantiated accusations or allegations.

Nonetheless, all comments represent only the opinions of those making them. The appearance of comments does not imply endorsement by the Health Care Renewal bloggers.

Please email general comments about the blog, other concerns, or questions to info AT firmfound DOT org